Xylazine in the Opioid Epidemic: A Systematic Review of Case Reports and Clinical Implications

Abstract

Introduction and objectives: The opioid overdose epidemic is exacerbated by the emergence of Xylazine as an illicit drug adulterant. Xylazine, a veterinary sedative, can potentiate opioid effects while also causing toxic and potentially fatal side effects. This systematic review aims to assess the impact of Xylazine use and overdoses within the opioid epidemic context. Method: A systematic search was conducted following PRISMA guidelines to identify relevant case reports, and case series related to Xylazine use. A comprehensive literature search included databases like Web of Science, PubMed, Embase, and Google Scholar, utilizing keywords and Medical Subject Headings (MeSH) terms related to Xylazine. Thirty-four articles met the inclusion criteria for this review. Results: Intravenous (IV) administration was a common route for Xylazine use among various methods, including subcutaneous (SC), intramuscular (IM), and inhalation, with overall doses ranging from 40 mg to 4300 mg. The average dose in fatal cases was 1,200 mg, compared to 525 mg in non-fatal cases. Concurrent administration of other drugs, primarily opioids, occurred in 28 cases (47.5%). Intoxication was identified as a notable concern in 32 out of 34 studies, and treatments varied, with the majority experiencing positive outcomes. Withdrawal symptoms were documented in one case study, but the low number of cases with withdrawal symptoms may be attributed to factors such as a limited number of cases or individual variation. Naloxone was administered in eight cases (13.6%), and all patients recovered, although it should not be misconstrued as an antidote for Xylazine intoxication. Of the 59 cases, 21 (35.6%) resulted in fatal outcomes, with 17 involving Xylazine use in conjunction with other drugs. The IV route was a common factor in six out of the 21 fatal cases (28.6%). Conclusion: This review highlights the clinical challenges associated with Xylazine use and its co-administration with other substances, particularly opioids. Intoxication was identified as a major concern, and treatments varied across the studies, including supportive care, naloxone, and other medications. Further research is needed to explore the epidemiology and clinical implications of Xylazine use. Understanding the motivations and circumstances leading to Xylazine use, as well as its effects on users, is essential for developing effective psychosocial support and treatment interventions to address this public health crisis.

Network pharmacology of xylazine to understand Its health consequences and develop mechanistic based remediations

“…Identification of high-affinity targets such as TRPM8, ADRA2A, ABCC9, RET, RAPGEF4 and ACHE aligns with recent reports on adverse effects associated with xylazine abuse, which are not classical of alpha-2 adrenergic receptor stimulation. 5,6,18,19,21 The tissue-specific expression of these targets, especially in the liver, adrenal gland and skeletal/smooth muscles, is also consistent with clinical observations of xylazine’s impact on microvasculature, endocrine and musculoskeletal systems. 4-6,8,18,19,21 This correlation supports the notion that the undesired effects of xylazine can be attributed to its interactions with the specific targets identified in this study.…”

“…5,6,18,19,21 The tissue-specific expression of these targets, especially in the liver, adrenal gland and skeletal/smooth muscles, is also consistent with clinical observations of xylazine’s impact on microvasculature, endocrine and musculoskeletal systems. 4-6,8,18,19,21 This correlation supports the notion that the undesired effects of xylazine can be attributed to its interactions with the specific targets identified in this study. The observation of xylazine interaction with KCNN2 and KCNH2 are consistent with most clinical reports of adverse cardiovascular effects in XUD patients.…”

“…The potential targets of xylazine identified in this study highlight its pharmacological profile, which is crucial to assessing the major adverse effects of xylazine reported in human XUD patients. 6,8,10,19 While the pharmacological effects of xylazine through the adrenergic receptors are well known, this study identifies several significantly higher affinity targets of xylazine, which are previously not reported. The highest average-affinities of xylazine to target categories such as hydrolases, kinases, transporters, and ion channels suggest a broad impact on several cellular processes potentially regulated by ABCC9, RET, RAPGEF4, ACHE, TGFBR1, PGR, KCNH2, KCNN2, and TRPM8.…”

“…The currently used treatment options for xylazine toxicity include, various combinations of intravenous (IV) fluids, saline ocular irrigation, mechanical ventilation, saline cathartics, gastric lavage, silver sulfadiazine cream / antibacterial ointments and/or yohimbine / tolazoline / atipamezole / naloxone (1.2 to 2 mg), lidocaine / atropine / magnesium infusion / activated charcoal / metoprolol succinate / thiamine / clonidine, all of which have shown only limited clinical efficacy in XUD patients. 1,3,4,6,9 Considering the current clinical limitations, the potential use of prazosin in reversing xylazine pharmacology suggested in this study offers a detailed mechanistic insights which merits its clinical evaluation. In comparison with other antagonists evaluated in this study, prazosin stands out as a particularly potent antagonist and hence evaluating its efficacy in XUD patients should be considered to validate prazosin’s effectiveness in real-world scenarios and explore its safety profile in diverse patient populations.…”

“…This study expands beyond the pharmacological effects of xylazine mediated by activation of alpha-2 adrenergic receptors and offers knowhow on possibilities of xylazine interacting with other targets with much superior affinity in humans. There are two major reasons to justify the study observations, 1) In human patients with xylazine use disorders (XUDs), the clinical symptoms observed are not classical of alpha-2 adrenergic receptor activation 4,6 and 2) The clinical approach to correcting adverse effects in XUD patients using alpha-2 adrenergic receptor antagonist show very poor efficacy. 1,4,9 These two reasons justify that the adverse effects observed in XUDs are mediated possibly by receptors other than alpha-2 adrenergic receptors and this study specifically identifies nine targets (ABCC9, RET, RAPGEF4, ACHE, TGFBR1, PGR, KCNH2, KCNN2 and TRPM8) which can be involved in XUDs.…”